An efficient method for the preparation of N-alkylamides from alkyl diphenylphosphinites and amides by using methyl acrylate

Article abstract of DOI:10.1246/cl.2006.456

N,N-Dibenzyltrifluoroacetamide was formed in good yield by treating benzyl diphenylphosphinite with N-benzyltrifluoroacetamide in the presence of easily available methyl acrylate under mild conditions. Yields obtained for the corresponding inverted sulfon

Full text of DOI:10.1246/cl.2006.456

456
Chemistry Letters Vol.35, No.4 (2006)
An Efficient Method for the Preparation of N-Alkylamides
from Alkyl Diphenylphosphinites and Amides by Using Methyl Acrylate
Hidenori Aoki and Teruaki Mukaiyamaꢀ
Center for Basic Research, The Kitasato Institute, 6-15-5 (TCI), Toshima, Kita-ku, Tokyo 114-0003
Kitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641
(Received February 1, 2006; CL-060140; E-mail: mukaiyam@abeam.ocn.ne.jp)
N,N-Dibenzyltrifluoroacetamide was formed in good yield
Table 1. Screening of ꢀ,ꢁ-unsaturated compounds on benzyla-
tion of N-benzyltrifuluoroacetamide
by treating benzyl diphenylphosphinite with N-benzyltrifluoro-
acetamide in the presence of easily available methyl acrylate
under mild conditions. Yields obtained for the corresponding
inverted sulfonamides were good to high in the cases when alkyl
diphenylphosphinites derived from chiral secondary alcohols
were used.
Ph POBn (1.1 equiv.)
2
(2.0 equiv.)
X
F C
3
NHBn
F C
3
NBn
2
CH Cl , rt, 24 h
2
2
O
O
(1.0 equiv.)
Yield/%
60
Yield/%
72
Entry
Entry
11
X
X
OPh
1
2
CN
Recently, it was reported from our laboratory that N-alkylat-
ed compounds were synthesized under neutral conditions by an
oxidation–reduction condensation using alkyl diphenylphos-
phinites (Ph2POR),1 2,6-di-tert-butyl-1,4-benzoquinone (DBBQ)
and weakly acidic compounds having a nitrogen–hydrogen bond
such as phthalimide, N-benzyltrifluoroacetamide or sulfon-
amides.2 Very recently, it was shown that the use of an alkyl di-
phenylphosphinite and an alkyl azide such as trimethylsilyl-
methyl azide or 1-azidoadamantane for the oxidant also could af-
ford the monoalkylated product from unsubstituted sulfonamide3
and nitrogen-containing cyclic compounds such as pyrrolidine
or piperidine derivatives.4 Although DBBQ and the azide com-
pounds efficiently behaved as the oxidants here, the price of
those reagents is not low. Therefore, our attention was focused
on establishing a practical and convenient method that uses
cheaper and simpler oxidants than DBBQ and azide compounds.
It is well known that an electron-rich trivalent phosphorus
compound such as trialkylphosphites readily undergoes a conju-
gate addition to the activated olefins such as ꢀ,ꢁ-unsaturated ni-
triles, esters, ketones, aldehydes, or amides in the presence of a
proton source such as an alcohol to furnish ꢁ-substituted phos-
phonate esters and ethers.5 Then, it was expected that an alkyla-
tion reaction onto nitrogen atom takes place if an alkyl diphenyl-
phosphinite and a weakly acidic compound having a nitrogen–
hydrogen bond are used in place of the above trialkylphosphite
and alcohol. However, no N-alkylation reactions have yet been
reported until present (Scheme 1).
O
O
Ot-Bu
N.R.
N.D.
12
13
53
63
CN
CN
Cl
O
3
4
O
N
N.R.
14
5
CN
O
Ph
5
6
7
N.R.
N.R.
15
16
3
CN
O
OMe
MeO
N.R.
CN
O
OMe
NC
N.D.
79
17
18
N.R.
CN
O
O
OMe
OMe
8
N.D.
MeO
O
O
OEt
OMe
9
73
73
19
20
40
50
O
O
OChx
a
OMe
10
O
O
aChx = Cyclohexyl.
Here, we would like to report a new method of high-yielding
N-alkylation of amides by using several alkyl diphenylphosphin-
ites with methyl acrylate under neutral conditions.
In the first place, N-benzylation of N-benzyltrifluoroacet-
amide by using 1.1 equiv. of benzyl diphenylphosphinite and
2.0 equiv. of acrylonitrile was tried and N,N-dibenzyltrifluoro-
acetamide was formed in 60% yield (Table 1, Entry 1). This re-
sult was found almost the same to that when DBBQ was used as
an oxidant (59% yield).2 Then, the use of other acrylonitrile de-
rivatives was studied next, but the expected product was not ob-
tained in any case (Entries 2–7). Then, other activated olefins
were tried in turn (Entries 8–20). Interestingly, the use of methyl
acrylate (MA) afforded the desired product in 79% yield whereas
no better results were found with other acrylic acid esters
(Entries 8–13). On the other hand, the yields remained low when
N,N-dimethylacrylamide and methyl vinyl ketone were used
(Entries 14 and 15). The corresponding targeted compounds
were obtained in moderate yields with the use of methyl propio-
late and methyl tetrolate while the desired product was not af-
forded when methyl acrylate derivatives were used (Entries
O
HNu
P
+
X
R
Nu
+
Ph
Ph POR
2
X
Ph
Scheme 1.
Copyright Ó 2006 The Chemical Society of Japan

Chemistry Letters Vol.35, No.4 (2006)
457
Table 2. N-Alkylations of sulfonamides with alkyl diphenyl-
phosphinites in the presence of methyl acrylate,a DBBQ,b or tri-
methylsilylmethyl azidec
Y
X
H
N
Ph POR
Ph
Ph
OR
2
P
OMe
OMe
1
2
1
2
1
2
NsNHR (1.0 equiv.)
Oxidant
R
R
R
R
R
R
Ph PCl
2
O
O
OH
OPPh
RNNs
2
1
1.1 equiv.
X
Y
d
Entry
Phosphinite
NsNHR
Oxidant
Yield/%
% ee
N
R
O
P
e
X
1
2
3
NsNHBoc
MA
83
77
44
72
46
59
94
91
43
67
43
98
98
97
96
92
95
98
99
98
97
93
Ph
Ph
O
OMe
R
N
+
P
OMe
Ph
DBBQ
Y
OPPh
Ph
2
O
TMSCH N
2
3
3
3
3
O
2
4
5
NsNH
MA
2
DBBQ
Scheme 2.
6
TMSCH N
2
with NsNHBoc8 was further studied under various conditions so
as to improve the enantiomeric excess (Table 3). As a result, it
was found that the desired product was obtained with 95% ee
if the reaction was carried out in benzene or toluene (Entries 5
and 6). Interestingly, the same result was also obtained if the
reaction was carried out in the absence of solvent at ꢁ10 ꢂC
(Entry 8).
A proposed reaction mechanism is shown in Scheme 2: An
alkyl diphenylphosphinite reacts initially with methyl acrylate to
form adduct 1 which is in turn transformed to the phosphonium
salt 2 by the interaction with an amide. An attack of thus formed
amide anion to the carbon atom adjacent to an oxygen atom of
the alkoxy group affords the corresponding amide along with
methyl 3-diphenylphosphinoylpropionate (3).9,10
Thus, it is noted that a simple and easily available methyl
acrylate was efficient to work as an oxidant in the preparation
of N-alkylated compounds from alkyl diphenylphosphinites
and weakly acidic compounds having a nitrogen–hydrogen
bond. Further study on this type of condensation reaction is
now in progress.
7
NsNHBoc
MA
Ph
8
DBBQ
OPPh
2
9
TMSCH N
2
10
11
NsNH
MA
2
DBBQ
12
13
14
15
16
17
18
TMSCH N
65
85
82
54
52
32
51
96
84
71
90
72
59
73
2
3
3
3
NsNHBoc
MA
DBBQ
Ph
OPPh
2
TMSCH N
2
f
NsNH
MA
DBBQ
2
TMSCH N
2
aMA (2.0 equiv.), CH2Cl2 (1.2 M), rt, 24 h. bDBBQ (1.1 equiv.),
CH2Cl2 (1.2 M), rt, 1 h. cTMSCH2N3 (1.1 equiv.), 1,2-dichloropro-
pane (0.6 M), 80 ꢂC, 6 h. dDAICEL CHIRALPAK AD–H column
was used for HPLC analysis. eEe was measured after deprotection
f
of Boc group. DAICEL CHIRALPAK AS–H column was used for
HPLC analysis.
16–20). Thus, it is noted that the methyl acrylate is the most
effective oxidant in this reaction.
Next, in order to confirm the usefulness of methyl acrylate,
reactions of 2-nitrobenzenesulfonamides6 with alkyl diphenyl-
phosphinites derived from chiral secondary alcohols were exam-
ined. The results are summarized in Table 2. For comparison, the
results obtained with DBBQ and trimethylsilylmethyl azide are
also listed.7
This study was supported in part by the Grant of the 21st
Century COE Program, Ministry of Education, Culture, Sports,
Science and Technology (MEXT), Japan.
References and Notes
Results shown in Table 2 demonstrate clearly that the
methyl acrylate gives better yields than any other oxidants. Good
enantiomeric excess was attained by using methyl acrylate
especially in the cases with (S)-sec-butyl diphenylphosphinite
and (R)-1-methyl-3-phenylpropyl diphenylphosphinite, while a
slightly lower enantiomeric excess was recorded in Entry 13
than that obtained with trimethylsilylmethyl azide (Entry 15).
Then, the reaction of (R)-1-phenylethyl diphenylphosphinite
1
For the preparation of alkyl diphenylphosphinites, See: K. Ikegai, W.
Pluempanupat, T. Mukaiyama, Chem. Lett. 2005, 34, 638.
T. Mukaiyama, H. Aoki, Chem. Lett. 2005, 34, 142.
H. Aoki, K. Kuroda, T. Mukaiyama, Chem. Lett. 2005, 34, 1266.
T. Mukaiyama, K. Kuroda, H. Aoki, Chem. Lett. 2005, 34, 1644.
R. G. Harvey, Tetrahedron 1966, 22, 2251.
T. Fukuyama, C.-K. Jow, M. Cheung, Tetrahedron Lett. 1995, 36, 6373.
General experimental procedure is as follows: To a stirred solution of an
amide (0.3 mmol) and an alkyl diphenylphosphinite (0.33 mmol) in
dichloromethane (0.25 mL) was added methyl acrylate (0.6 mmol) at
room temperature under argon atmosphere. The reaction mixture was
stirred for 24 h at room temperature. After completion of the reaction
(detected by TLC), it was purified by preparative TLC to afford the
corresponding N-alkyl amide.
2
3
4
5
6
7
Table 3. The reaction of NsNHBoc with (R)-1-phenylethyl di-
phenylphosphinite using methyl acrylate
Ph
Ph
NsNBoc
MA (2.0 equiv.)
Solv., rt, 24 h
NsNHBoc
+
8
9
T. Fukuyama, M. Cheung, T. Kan, Synlett 1999, 1301.
OPPh2
(1.1 equiv.)
Spectral data for 3; IR (ATR, cmꢁ1) 3055, 2948, 1742, 1436, 1239,
1174, 1166, 742, 694, 533, 507, 449, 427; 1H NMR (270 MHz, CDCl3)
ꢂ7.78–7.71 (m, 4H), 7.57–7.44 (m, 6H), 3.63 (s, 3H), 2.70–2.55 (m, 4H);
13C NMR (68 MHz, CDCl3) ꢂ172.6 (d, J ¼ 16:8 Hz), 132.1 (d, J ¼
99:5 Hz), 131.8 (d, J ¼ 2:8 Hz), 130.6 (d, J ¼ 9:5 Hz ), 128.6 (d, J ¼
11:7 Hz), 52.0, 26.3 (d, J ¼ 2:2 Hz), 25.1 (d, J ¼ 72:7 Hz); HRMS
(APCIþ) calcd for C16H18O3P [M + H]þ 289.0994, found m/z
289.0990.
Entry Solvent Yield /% % ee
Entry Solvent Yield /% % ee
1
2
3
4
CH2Cl2
CHCl3
THF
85
87
71
84
91
84
89
5
6
7a
8a,b
Benzene
Toluene
None
85
81
88
88
95
95
93
95
1,4-Dioxane 84
None
a12.0 equiv. of methyl acrylate was used. bThe reaction was carried out
at ꢁ10 ꢂC.
10 A. Bell, A. H. Davidson, C. Earnshaw, H. K. Norrish, R. S. Torr, D. B.
Trowbridge, S. Warren, J. Chem. Soc., Perkin Trans. 1 1983, 2879.
Published on the web (Advance View) March 25, 2006; DOI 10.1246/cl.2006.456